Predicting Physical Stabilityin Q1A(R)

Chi-wan Chen, Ph.D.Office of New Drug Chemistry

Center for Drug Evaluation and ResearchFood and Drug Administration

Pharmaceutical ScienceAdvisory CommitteeNovember 28, 2001

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Stress Testing of Drug Substance

• Elevated temperature (in 10°C increment above accelerated temperature)

• Humidity (75% or greater)

• Effect of pH

• Oxidation

• Light

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Batch Selection of Drug Product

• A minimum of 3 batches: 2 should be at least pilot scale; 3rd can be smaller

• Same formulation and container/closure as proposed for marketing

• Using manufacturing process simulating that for production batches

• Meeting same specifications as proposed for marketing

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Test Specification

• Q1AR: Attributes that are susceptible to change during storage and likely to influence quality, safety, and/or performance

• Q1AR: Physical, chemical, microbiological, and biological attributes; functionality test

• Q3A/B: Identification and qualification of impurities/degradation products

• Q6A: Establishing acceptance criteria for polymorphic forms, particle size, dissolution

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Room Temperature Storage Conditions

Study

Long-term

Accelerated

Intermediate

Storage Condition

25°C ± 2°C/ 60% RH ± 5% RH

40°C ± 2°C/ 75% RH ± 5% RH

30°C ± 2°C/ 60% RH ± 5% RH

Data at submission

12 mos from an ongoing study

6 mos from a 6-mo study

6 mos from a 12-mo study

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Low Temperature Storage Conditions

Study

• Refrigerator

Long-term

Accelerated

• FreezerLong-term

Accelerated**(optional)

Storage Condition

5°C ± 3°C

25°C ± 2°C/60% RH ± 5% RH

-20°C ± 5°C

5°C ± 3°C or 25°C ± 2°C

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Significant Change Criteria

• 5% change in assay, or failure to meet acceptance criteria for potency using biological or immunological procedures

• Degradation products exceeding acceptance criteria

• Failure to meet pH acceptance criteria

• Failure to meet acceptance criteria for appearance, physical attributes, functionality test

• Failure to meet acceptance criteria for dissolution for 12 dosage units

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Consequence of Significant Change

• If significant change occurs at accelerated condition, conduct intermediate testing, where applicable; extrapolation of shelf life beyond real-time data may not be granted

• If significant change occurs at intermediate condition, consider reformulation, more protective container/closure, shorter shelf life, qualification of higher impurity level

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Shelf Life Establishment

• Extrapolation of shelf life beyond real-time data can be granted if no significant change at accelerated condition and if supported by supporting data and/or statistical analysis

• Post-approval, tentative shelf life should be confirmed by 3 production batches on stability

• In the U.S., at least one batch should be put on long-term stability annually thereafter

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Predictability of Physical Stability

• Predictability of long-term behavior based on physical attributes at accelerated condition

• Predictability of future production batch behavior based on data from primary stability batches– Complexity of formulation and dosage form– Robustness of manufacturing process, scale-up– Soundness of sampling plan– Reproducibility of analytical procedure– Meaningful acceptance criteria– Experience; number of primary and supporting batches